A number of disease states require chronic transfusion of RBCs, including sickle cell anemia, alpha and beta thalassemia, aplastic anemia, renal failure, myeloproliferative disorders, bone marrow and solid organ transplantation and chronic anemia of various etiologies. However, a major impediment to the use of chronic RBC transfusion therapy is the induction of alloantibodies to blood group antigens present on donor RBCs but absent on recipient erythrocytes (RBC alloimmunization). When chronically transfused patients accumulate enough clinically significant antibodies that essentially all available units are incompatible, the patient is required to either forego the beneficial and/or life saving effects of transfusion or receive a unit of "least incompatible" blood, risking a potentially fatal hemolytic transfusion reaction. Thus, the development of antibodies to blood group antigens is a serious problem that can be a matter of "life and death" in chronically transfused patients. Interestingly, despite the presence of hundreds of blood group antigens on transfused RBCs, some patients do not become alloimmunized while others make strong antibody responses to foreign RBC antigens. The factors and mechanisms that determine whether a transfused patient will be alloimmunized are poorly understood. Using a novel murine model of RBC immunization, we have observed that recipient inflammation plays a pivotal role in antibody responses to transfused RBCs and that distinct sub-types of inflammation can result in a significant enhancement of both the frequency and magnitude of RBC immunization. Moreover, RBC transfusion in uninflammed recipients not only fails to elicit an antibody response, but leads to immunological tolerance. These findings suggest a novel mechanism for regulation of antibody responses to transfused RBCs in humans, and to the best of our knowledge, provide the first evidence of the role of inflammation in RBC immunization. The overall objective of these studies is to generate a detailed mechanistic understanding of how recipient inflammation regulates immunity vs. tolerance to antigens on transfused RBCs. The data generated will both further our basic understanding of RBC immunization and lay the technical and conceptual groundwork for the rational development of therapeutic interventions to prevent RBC immunization.